Genetic studies have implicated the SLAM family in Systemic lupus erythematosus (SLE), but the[unreadable] functional roles of specific gene(s) within the SLAM locus in SLE are not yet clear. Our recent studies[unreadable] show that CD48 deficient (-/-) mice backcrossed onto the C57BL/6 (B6) background from the 129Sv[unreadable] background for 12 generations develop a lupus-like syndrome. By 6 months of age, these CD48-/- mice[unreadable] develop activated T and B cells, anti-nuclear antibodies, immune complexes and glomerulonephritis. We[unreadable] also have found that there are defects in T cell tolerance in CD48-/- mice. There are 2 potential[unreadable] explanations for the development of the SLE phenotype: Disease could be caused by the absence of[unreadable] CD48, or due to epistatic interactions between 129Sv genes flanking the disrupted CD48 gene and B6[unreadable] genes in the CD48-/- mouse strain. The goal of Project 3 is to investigate the role of CD48 in SLE. As a[unreadable] definitive tool to understand the essential functions of CD48, we will use CD48-/- B6 mice generated by[unreadable] homologous recombination using B6 ES cells. Our specific aims are: 1) To test the hypothesis that[unreadable] CD48 regulates antigen-specific CD4 T cell activation and tolerance. We will examine if there are[unreadable] intrinsic T cell defects and/or dysregulated interactions between APC and T cells. We also use CD244-/-[unreadable] mice to investigate whether the CD48 ligand, CD244, regulates T cell responses. This focus on CD244[unreadable] is driven by genetic studies of Project 1 that implicate CD244 variation in human SLE and preliminary[unreadable] data that suggest CD244 on the APC may regulate T cell: APC interactions. 2) To test the hypothesis[unreadable] that CD48 regulates B cell activation and/or B cell tolerance. We will determine if there are B cell[unreadable] intrinsic defects, examine humoral immune responses, and generate CD48-/- VH3H9 transgenic mice to[unreadable] study the role of CD48 in regulating anti-dsDNA B cells. 3) To investigate the hypothesis that CD48[unreadable] regulates the development of SLE. We determine whether SLE develops in B6 CD48-/- mice. If SLElike[unreadable] disease develops, then we will evaluate the function of CD48 on the T cell, B cell and other cell[unreadable] types in SLE. If SLE does not develop, we will test the hypothesis that CD48-/-(129Sv x B6)BC12 CD48-[unreadable] /- mice develop SLE due to flanking 129Sv SLAM family genes and not due to the disrupted CD48 gene,[unreadable] by introducing a 129Sv BAG with a normal or disrupted 129Sv CD48 gene into the CD48-/- C57BL/6[unreadable] mouse and assess whether the resulting strains develop SLE. This PPG facilitates collaborative[unreadable] interactions and provides a number of important tools and approaches that will enable us to address[unreadable] these important issues. These studies should contribute to the overall goal of this PPG: to understand[unreadable] how SLAM family members control pathways that regulate the development of SLE.